DESCRIPTION (APPLICANT'S ABSTRACT): It has been suggested that ReqQ-associated diseases may link genomic stability, cancer and aging. However, the functions of RecQ helicases are still unknown. Sgs1 (also known as top 3 slow growth suppressor) is the only RecQ helicase in S. cerevisiae. David Sinclair is a new investigator who has identified two separable functions for Sgs1 in telomere maintenance and has also shown that mouse WRN (another RecQ helicase) can substitute for Sgs1 function. The investigator has observed that telomerase negative yeast cells lacking Sgs1 senesce more rapidly (possess only 40 percent lifespan of wild type cells) due to accelerated telomere attrition. The mechanism involves movement of telomere proteins (SIRs) to the nucleolus causing rDNA instability and fragmentation. In addition, cells lacking Sgs1 are unable to recover efficiently from senescence, are completely defective in the type II ALT pathway, and rare survivors grow poorly. Lastly, another function of Sgs1 may involve telomere capping in cells that engage the ALT pathway. The focus of this proposal is to characterize the role of Sgs1 in telomere maintenance and to understand more about how alternative pathways to telomerase are regulated. The experiments proposed should provide insights into function of human RecQ helicases (mutations of which may be important in human diseases such as Werner's, Bloom's and Rothmund-Thomson syndromes) and how cancer cells may be able to proliferate in the absence of telomerase.